Phenotypic characterization of a large European family with Brugada syndrome displaying a sudden unexpected death syndrome mutation in SCN5A:

INTRODUCTION: Brugada syndrome is characterized by sudden death secondary to malignant arrhythmias and the presence of ST segment elevation in leads V(1) to V(3) of patients with structurally normal hearts. This ECG pattern often is concealed but can be unmasked using potent sodium channel blockers. Like congenital long QT syndrome type 3 (LQT3) and sudden unexpected death syndrome, Brugada syndrome has been linked to mutations in SCN5A. METHODS AND RESULTS: We screened a large European family with Brugada syndrome. Three members (two female) had suffered malignant ventricular arrhythmias. Ten members showed an ECG pattern characteristic of Brugada syndrome at baseline, and eight showed the pattern only after administration of ajmaline (total 12 female). Haplotype analysis revealed that all individuals with positive ECG at baseline shared the SCN5A locus. Sequencing of SCN5A identified a missense mutation, R367H, previously associated with sudden unexpected death syndrome. Two of the eight individuals who displayed a positive ECG after the administration of ajmaline, but not before, did not have the R367H mutation, and sequencing analysis failed to identify any other mutation in SCN5A. The R367H mutation failed to generate any current when heterologously expressed in HEK cells. CONCLUSION: Our results support the hypothesis that (1) sudden unexpected death syndrome and Brugada syndrome are the same disease; (2) male predominance of the phenotype observed in sudden unexpected death syndrome does not apply to this family, suggesting that factors other than the specific mutation determine the gender distinction; and (3) ajmaline may provide false-positive results. These findings have broad implications relative to the diagnosis and risk stratification of family members of patients with the Brugada syndrome.     

SCN5A基因移码突变导致Brugada综合征

目的：检测Brugada综合征的致病基因突变位点。方法：对1个Brugada综合征家系11名成员和20名正常人的DNA样本应用双脱氧链终止基因测序法进行心脏钠离子通道α亚单位（voltage-gated sodium channel type V,SCN5A)基因测序。结果：SCN5A基因测序发现Brugada综合征家系第22个外显子存在1个杂合基因移码突变位点，经克隆传代后测序发现该突变为4087insC。该突变使通道蛋白1314－1317位氨基酸发生改变并在1318位终止，导致钠离子通道第3结构域S4结构变化，S5－6及第4结构域全部缺失。该突变在Brugada综合征家系中分布符合常染色体显性分布规律。对照组未发现相同突变。结论：SCN5A基因4087insC是国内首次发现的导致Brugada 综合征的基因突变位点，也是国际上发现的第2个引起Brugada综合征的SCN5A基因移码突变     

A balanced translocation disrupting SCN5A in a family with Brugada syndrome and sudden cardiac death

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Identification of a SCN5A founder mutation causing sudden death,Brugada syndrome,and conduction blocks in Southern Italy

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Brugada综合征相关基因SCN5A新突变位点的检测

目的 研究中国人Brugada综合征相关基因SCN5A突变情况。方法 利用多聚酶链反应及DNA测序对1个Brugada综合征家系SCN5A基因的全部28个外显子进行基因检测。结果 在国内外已知突变点均无突变，发现1个新的错义突变位点(A5471G)，其相应的氨基酸改变为N1774S。结论 在中国人Brugada综合征患者的SCN5A基因上发现1个新的突变位点。     

Brugada syndrome with a novel missense mutation in SCN5A gene: A case report from Bangladesh

Brugada syndrome is an inherited cardiac arrhythmia that follows autosomal dominant transmission and can cause sudden death. We report a case of Brugada syndrome in a 55-year-old male patient presented with recurrent palpitation, atypical chest pain and presyncope. ECG changes were consistent with type 1 Brugada. Gene analysis revealed a novel missense mutation in SCN5A gene with a genetic variation of D785N and a nucleotide change at 2353G-A. One of his children also had the same mutation. To our knowledge this is the first genetically proved case of Brugada syndrome in Bangladesh.     

Risk stratification of sudden cardiac death in asymptomatic female Brugada syndrome patients: A literature review

Background and Objectives

Risk stratification in Brugada syndrome remains a difficult problem. Given the male predominance of this disease and their elevated risks of arrhythmic events, affected females have received less attention. It is widely known that symptomatic patients are at increased risk of sudden cardiac death (SCD) than asymptomatic patients, while this might be true in the male population; recent studies have shown that this association might not be significant in females. Over the past few decades, numerous markers involving clinical symptoms, electrocardiographic (ECG) indices, and genetic tests have been explored, with several risk-scoring models developed so far. The objective of this study is to review the current evidence of clinical and ECG markers as well as risk scores on asymptomatic females with Brugada syndrome.

Findings

Gender differences in ECG markers, the yield of genetic findings, and the applicability of risk scores are highlighted.

Conclusions

Various clinical, electrocardiographic, and genetic risk factors are available for assessing SCD risk amongst asymptomatic female BrS patients. However, due to the significant gender discrepancy in BrS, the SCD risk amongst females is often underestimated, and there is a lack of research on female-specific risk factors and multiparametric risk scores. Therefore, multinational studies pooling female BrS patients are needed for the development of a gender-specific risk stratification approach amongst asymptomatic BrS patients.     

SCN5A mutation associated with cardiac conduction defect and atrial arrhythmias

INTRODUCTION: We aimed at identifying the molecular defect underlying the clinical phenotype of a Finnish family with a cardiac conduction defect and atrial arrhythmias. METHODS AND RESULTS: A large Finnish family was clinically evaluated (ECG, 24-hour ambulatory ECG, echocardiography). We performed linkage analysis with markers flanking the SCN5A gene and subsequently sequenced the SCN5A gene. Five family members had atrial arrhythmias and intracardiac conduction defects, and due to bradycardia needed a pacemaker when adolescents. No heart failure or sudden cardiac death was observed. Left ventricle dilatation was seen in one individual and three individuals had a slightly enlarged right ventricle. Premature death due to stroke occurred in one subject during the study, and two other members had suffered from stroke at young age. Linkage analysis favored the role of the SCN5A gene in disease pathogenesis, and direct sequencing disclosed D1275N mutation. This alteration was present not only in all six affected individuals, but also in two young individuals lacking clinical symptoms. CONCLUSIONS: Cardiac conduction defect and atrial arrhythmias in a large Finnish family appear to result from the SCN5A D1275N mutation. Although no sudden cardiac death was recorded in the family, at least three affected members had encountered brain infarction at the age of 30 or younger.     

A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill

Mutations in the cardiac Na+ channel gene SCN5A are responsible for multiple lethal ventricular arrhythmias including Brugada syndrome and congenital long QT syndrome. Here we report a case of Brugada syndrome with ST elevation in the right precordial and inferior leads accompanied by atrial standstill and spontaneous ventricular fibrillation. Atrial standstill and J wave elevation were provoked by procainamide. Genetic analysis revealed a missense mutation (R367H) in SCN5A. The resultant mutant Na+ channel was nonfunctional when expressed heterologously in Xenopus oocytes. Our study suggests that genetic defects in SCN5A may be associated with atrial standstill in combination with ventricular arrhythmias.     

SCN5A基因突变与青壮年猝死综合征

青壮年猝死综合征(SUNDS)的病因迄今不明。随着分子遗传学和心脏离子通道研究的深入,SCN5A基因突变已被确定为Brugada综合征、3型长QT间期综合征的最重要病因。本文综述文献,结合项目组研究,介绍SCN5A基因突变与SUNDS发生的相关性。     

中国散发Brugada综合征患者SCN5A基因突变位点的检测

目的 对5例中国散发Brugada综合征患者进行SCN5A基因突变位点检测.方法 采用直接测序法对5例散发Brugada综合征患者进行SCN5A基因碱基突变位点的检测,测序结果用Chromas软件进行BLAST分析,再将测序峰与网上检索结果重新比对.结果 1例Brugada患者发现了一个同义杂合变异,即SCN5A基因第20外显子上发现一个碱基变异（C3549T）,其所编码的第1 183位苏氨酸没有发生改变（T1183T）.结论 在中国散发Brugada综合征患者的SCN5A基因上发现了1个新的碱基杂合同义突变.     

Ventricular tachycardia in a Brugada syndrome patient caused by a novel deletion in SCN5A

The aim of the present study was to identify the molecular mechanism behind ventricular tachycardia in a patient with Brugada syndrome. Arrhythmias in patients with Brugada syndrome often occur during sleep. However, a 28-year-old man with no previously documented arrhythmia or syncope who experienced shortness of breath and chest pain during agitation is described. An electrocardiogram revealed monomorphic ventricular tachycardia; after he was converted to nodal rhythm, he spontaneously went into sinus rhythm, and showed classic Brugada changes with coved ST elevation in leads V₁ to V₂. Mutation analysis of SCN5A revealed a novel mutation, 3480 deletion T frame shift mutation, resulting in premature truncation of the protein. Heterologous expression of this truncated protein in human embryonic kidney 293 cells showed a markedly reduced protein expression level. By performing whole-cell patch clamp experiments using human embryonic kidney 293 cells transfected with the mutated SCN5A, no current could be recorded. Hence, the results suggest that the patient suffered from haploinsufficiency of Na_v1.5, and that this mutation was the cause of his Brugada syndrome.     

中国一家系Brugada综合征相关基因SCN5A突变位点的检测

目的研究一个中国家系Brugada综合征相关基因SCNSA的突变情况。方法收集一个Brugada家系的临床资料,采用聚合酶链反应及直接测序法对该家系进行SCN5A基因突变检测,同时对136例家系外健康对照者的该位点进行单链构象多态性分析。结果在Brugada家系中发现了两个杂合变异,即SCN5A基因第二外显子上发现一个同义变异（A129G）,没有导致氨基酸的改变（A29A）;第26外显子发现一个错义变异（T4492A）,导致代表酪氨酸的1494位密码子突变为天门冬酰胺（Y1494N）。结论在中国人Brugada综合征患者的SCNSA基因上发现了一个已经报道的同义多态位点（A29A）及一个新的错义突变位点（Y1494N）。     

Homozygous SCN5A mutation in Brugada syndrome with monomorphic ventricular tachycardia and structural heart abnormalities.

AIMS: To describe a patient showing monomorphic ventricular tachycardia, ECG aspect of Brugada syndrome, and structural heart abnormalities due to a homozygous missense mutation in SCN5A. METHODS AND RESULTS: Thirteen subjects (six males, seven females, mean age 46 +/- 22 years) belonging to the same family underwent physical examination, basal biochemical marker detection, 12-lead ECG, Holter ECG, signal-averaged ECG, echocardiogram and genetic analysis. The proband underwent a stress test together with left and right ventricular angiography and electrophysiological study. Three subjects (the proband, his mother, and one brother) showed on ECG an ST-segment elevation in the right precordial leads with coved type aspect. Moreover, the proband presented a sustained monomorphic ventricular tachycardia (left bundle branch block aspect with superior axis), whereas all other family members were asymptomatic. Imaging techniques documented right ventricular structural abnormalities only in the proband. Mutation screening in SCN5A gene was performed in the proband and in available family members. The proband carries a novel SCN5A mutation, R814Q, in homozygous, whereas the parents and four siblings were heterozygous carriers of the same mutation. CONCLUSION: This study provides the first evidence of a homozygous missense mutation in SCN5A associated with atypical ventricular arrhythmias and right structural abnormalities.     

A novel missense mutation in the SCN5A gene associated with Brugada syndrome bidirectionally affecting blocking actions of antiarrhythmic drugs

Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha subunit, which can lead ventricular fibrillation and sudden death. Inattentive use of antiarrhythmic drugs potentially triggers fatal cardiac arrhythmias through further reduction of sodium current (I(Na)). We studied the molecular mechanism underlying a case of Brugada syndrome that showed no response to a class Ic antiarrhythmic drug. Molecular genetic studies of a patient with Brugada syndrome identified a novel mutation in SCN5A, which causes substitution of serine for asparagine (N406S) in S6 of domain I (IS6). The provocation test with pilsicainide, a class Ic antiarrhythmic drug, failed to exacerbate ST-segment elevation in this case. Electrophysiological analyses of the N406S-mutant channel expressed together with the beta1 subunit in HEK293 cells showed that the voltage dependence of activation was positively shifted by 16 mV and that intermediate inactivation was enhanced. Whereas tonic block by pilsicainide was not changed in the N406S channel, use-dependent block by pilsicainide was almost completely abolished, consistent with the clinical findings of the negative provocation test. In contrast, the N406S channel showed stronger use-dependent block by quinidine than the wild-type channel. We demonstrate a novel Brugada mutation N406S, which is associated with the discordant effects on blocking actions of antiarrhythmic drugs as well as the multiple channel gating defects. We emphasis that an antiarrhythmic drug may exert unpredicted effects in patients with channel mutations.